2,3,7,8-Tetrachlorodibenzo-p-dioxin is the prototype of a group of halogenated aromatic hydrocarbons (HAH) that are widespread and persistent environmental pollutants. Animals exposed to TCDD exhibit a range of toxic effects including alterations in metabolic pathways, immunological changes, teratogenic effects, and neoplasia. Epidemiological studies demonstrate that exposure to TCDD causes skin lesions and possibly increased risks for some forms of cancer in human population. Ah (Aromatic hydrocarbon) receptor (AhR) is a bHLH transcription factor which, together with other proteins, mediates the biological effects of TCDD. The overall goal of the proposed project is to identify new protein partners for the Ah receptor. The specific aims of the study are: (1) identification of the receptor's functional domains, with emphasis on domains responsible for binding HLH protein(s), transcription activation, and transcription inhibition; (2) identification, cloning, and characterization of proteins (other than Arnt) that interact with and modulate the functions of the Ah receptor. This research will provide a better understanding of the mechanism by which TCDD elicits its biological effects in vivo. This knowledge may help to resolve uncertainty in assessing the risk that TCDD poses to human health.